Method for conducting maintenance on a chromatography column

ABSTRACT

The present invention relates to methods for conducting maintenance on chromatography columns used in industrial-scale chromatography. In particular, the invention is concerned with safer methods for performing maintenance on such columns, such as cleaning and replacing bed supports, distributors, nozzles, O-rings and other column components, by the use of a handling device to support, lift, carry and manipulate such column components.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/834,864 filed Aug. 7, 2007, now U.S. Pat. No. 7,780,853, which is acontinuation-in-part of U.S. patent application Ser. No. 11/763,477, nowU.S. Pat. No. 7,708,891; the entire disclosure of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods for conducting maintenance onchromatography columns used in industrial-scale chromatography. Inparticular, the invention is concerned with safer methods for performingmaintenance on such columns, such as cleaning and replacing bedsupports, distributors, O-rings and other column components, by the useof a handling device to support, lift, carry and manipulate such columncomponents.

BACKGROUND OF THE INVENTION

Chromatography columns may be used in industrial processes to purifyprocess liquids and separate substances of interest from processliquids; typical examples include large-scale preparative purificationof fine chemicals and pharmaceuticals, together with biologicalproducts.

Industrial-scale chromatography columns typically comprise a hollow,axially vertical tubular housing including a liquid inlet at the upperend and through which the buffer and substances to be separated aredispensed to the media bed located within the cavity of the tube, and aliquid collecting system at the lower end for collecting substances andbuffer. The particulate chromatographic media or bed through which thebuffer fluid and/or substances to be separated and purified percolatesis located between the liquid inlet and collecting system.

An adapter assembly is typically affixed to the upper end of the tubularhousing and a base assembly to the lower end where it is bolted to thebottom flanges. Each of these assemblies typically comprises a strongbacking plate and a distributor plate which further supports a bedsupport; a bed support is a layer of mesh, screen, filter, sinter orother fluid-permeable media-retaining material which permits processliquid flow into and out of the chromatography bed space or cavity whileretaining the bed of particulate medium. To provide adjustability andcontrol of the bed height and bed compression, the adapter assembly istypically made in the form of a piston or sliding adapter in the columntube interior. After the column is charged with bed media, typicallythrough a nozzle, the adapter may be forced toward the bottom of thetube to compress or pressurize the media bed. Generally the baseassembly is a fixed structure which is bolted against the bottom flangeof the column tube but, in some instances, may also be in the form of amovably slidable piston or adapter.

The backing plate of the base assembly generally acts as a support forthe column, being itself supported on legs or some other standarrangement which allows clearance for outlet pipework projectingbeneath the base assembly.

When such a column requires maintenance to, or cleaning of, internalcomponents, such as the valves, seals, meshes/screens, distributionsystems etc., heavy lifting gear such as a crane or hoist is necessaryto lift the upper end/adapter assembly away from the column tube and thecolumn tube away from the lower end/base assembly as these assembliescan weigh in excess of three tons. Lifting of these assemblies thenprovides access to the internal column components, but often it isnecessary to remove some of these components prior to maintenance. Asthese components can be very heavy (bed supports, for example, may weighin excess of 100 kg), their manual removal and re-introduction poses apotential safety risk to operators who must physically support andmanipulate them.

The use of heavy overhead lifting equipment to disassemble the column inorder to carry out internal maintenance is, in itself, highlyundesirable. Operator safety is obviously a concern when heavy equipmentis lifted overhead and technicians exposed below. Furthermore, alignmentstructures are required to keep the column and its base/adapterassemblies axially aligned as they are separated from each other, toavoid damage to the precision components. Moreover, the requirement touse heavy lifting equipment imposes constraints on housing such columns,sufficient overhead space and support being required to accommodatehoists or cranes. Further, the presence of such hoists or cranes in GMPfacilities used for biopharmaceutical manufacturing (such facilitiesalso being known as “clean rooms”) is highly undesirable due to theshedding of particulate matter such as dirt during their operation andmaintenance.

U.S. Pat. No. 6,736,974 addresses some of the above problems byproviding a column which is capable of lifting the adapter assemblyabove the column tube and/or raising the column tube above the baseassembly by means of an hydraulic system which is integral to thecolumn.

However, the system described in U.S. Pat. No. 6,736,974 has significantdisadvantages associated with it by virtue of its design. As can be seenfrom FIGS. 4 and 5 of U.S. Pat. No. 6,736,974 and described in column 4,lines 63-66 of that document, in order to remove the distributor plate(31) and/or bed support/mesh (28/60) from the interior of the column,the operator must work within the centre of the drum (18) to access andremove the fixing nut (30) which secures these component parts. Asindustrial columns typically have diameters ranging from about 200 mm to2000 millimeters, this means that the operator must work below asuspended or supported load to unscrew the nut. This clearly poses asignificant safety risk to the operator, particularly where theoperator's arm or head is exposed below the suspended or supported load.

Furthermore, once the column tube/cylinder or adapter assembly has beenraised from the base assembly or tube, respectively, removal of theheavy bed support or distributor from the column can only beaccomplished by tilting the bed support or distributor at an angle tonegotiate the hydraulic drive pistons or safety rods. This can clearlybe seen from, for example, FIGS. 3, 4 and 5 in which the distancebetween any two safety rods (69) or between any two hydraulic pistons(36) is less than the diameter of the bed support/mesh (28/60) ordistributor plate (31). The same problem would exist for the base oradapter bed support (not shown). Removal of these internal components,which could weigh in excess of 100 kg, requires considerable manhandlingby the operator and necessitates their being exposed below the suspendedcolumn or adapter assembly. Once again, this represents a significantsafety risk for the operator.

The task of physically removing the heavy bed support or distributor, asdescribed in U.S. Pat. No. 6,736,974, must be carried out by anoperator, there being no disclosure of the use of any lifting aid toassist in this task. The configuration of the hydraulic pistons and thesafety rods, and the need to tilt the bed support and/or distributor inorder to avoid the supporting structures in withdrawing these componentsfrom the column, makes their manual withdrawal and re-introduction adifficult and potentially dangerous task.

WO 2005/056156 (Euroflow (UK) Limited) also discloses a column which canbe accessed for maintenance without the need for a crane or hoist. Thecolumn is designed such that the tube and the base assembly can beseparated by means of hydraulic drive cylinders to provide an accessspace between them to conduct maintenance or service on the baseassembly. The piston of the adapter assembly can be advanced through thecolumn tube to expose it at the open end of the column tube, i.e. in thespace between the tube and the base assembly, for maintenance.

However, as is evident from this document (for example, FIGS. 19 and 20and related description on page 23) access to release the fasteningscrews retaining the bed support/mesh in place is provided by the spacebetween the tube and the base assembly. Removal of the bed support/meshnecessitates the operator being exposed to a suspended load whileretaining screws are removed. Furthermore, the distance between any twodrive cylinders for maintenance access is less than the diameter of thebed support (see, for example, FIG. 7), which requires the operator tomanhandle and tilt the mesh or bed support when removing or replacingit. Once again, there is no mention of the use of a handling device inthe removal or re-introduction of column components. Maintenance of thecolumn thus imposes a potential safety risk for the operator inphysically supporting and manipulating the heavy column components.

U.S. Pat. No. 7,708,891, entitled “Chromatography Column and Method ofMaintenance”, filed by the same applicants and hereby incorporated byreference in its entirety, describes a chromatography column whichaddresses some of the above problems.

Accordingly, a need exists to improve the maintenance methods availablefor chromatography columns by providing devices which facilitate thehandling, manipulation and transportation of heavy column componentswithout the need to work under suspended loads and thereby reduce therisk of operator error and injury.

SUMMARY OF THE INVENTION

The present invention recognizes and addresses these needs and others.In a first aspect of the present invention, there is provided a methodfor conducting maintenance on a chromatography column comprising thesteps of:

-   -   a) providing a chromatography column comprising;        -   a dispersion system comprising a nozzle including a mobile            phase pathway connected to a liquid inlet;        -   a tube with an adaptor assembly, said adapter assembly            moveable within a cavity of said tube in an operational            mode;        -   the adapter assembly comprising, a distributor and a bed            support fastened to each other by releasable fixing means,        -   a collection system opposing the dispersion system; and one            or more seals;    -   b) disconnecting the adapter assembly from the tube;    -   c) lifting the adapter assembly above the tube to provide a gap        for access therebetween;    -   d) unfastening the bed support from the distributor by releasing        the fixing means;    -   e) removing the bed support from the column with a handling        device;    -   f) conducting maintenance on the column and/or the bed support        and/or said one or more seals;    -   g) returning the bed support to the column with said handling        device and fastening the bed support to the distributor; and    -   h) lowering the adapter assembly to an operational position        within the tube and reconnecting the adapter assembly to the        tube.

In one aspect, the method further comprises the step of removing thedistributor from the column with the handling device and conductingmaintenance on the column and/or said distributor.

In one aspect, the method further comprises the steps of removing saidnozzle from the column with the handling device prior to step d) andreturning the nozzle to the column with the handling device followingstep g).

Preferably, the handling device is in the form of a cart having a pillarand comprising one or more arms projecting from said pillar forsupporting the bed support or the distributor or the nozzle thereon.Preferably, the arms are extendable from the pillar. More preferably,the arms are vertically movable on the pillar.

In one aspect, lifting the adapter assembly in step c) and/or loweringthe adapter assembly in step h) is carried out by means of an overheadhoist or crane.

In another aspect, lifting the adapter assembly in step c) and/orlowering the adapter assembly in step h) is carried out by means of adrive system comprising one or more cylinders which are mounted to orare integral with the column.

Optionally, the method additionally comprises the step of removing saidone or more cylinders from the column with the handling device.

Preferably, the step of removing the bed support from the column and/orthe step of returning the bed support to the column with the handlingdevice is carried out without substantially tilting the bed support.This reduces operator exposure beneath the suspended load andfacilitates mechanical handling of the bed support. The term ‘withoutsubstantially tilting’ as used herein means ‘tilting at an angle of nomore than 5° to the horizontal’.

Optionally, the step of removing the bed support from the column and/orthe step of returning the bed support to the column with the handlingdevice is carried out by tilting the bed support at an angle of morethan 5° to the horizontal. This may be necessary where the distancebetween any two drive cylinders is less than the diameter of the bedsupport.

In a second aspect of the present invention, there is provided a methodfor conducting maintenance on a chromatography column comprising thesteps of:

-   -   a) providing a chromatography column comprising;        -   a dispersion system comprising a nozzle including a mobile            phase pathway connected to a liquid inlet;        -   a tube with an adapter assembly and a base assembly, said            adapter assembly moveable within a cavity of said tube in an            operational mode;        -   the base assembly comprising a distributor and a bed support            fastened to each other by releasable fixing means;        -   a collection system opposing the dispersion system; and one            or more seals;    -   b) releasing the tube from the base assembly;    -   c) lifting the tube and the adapter assembly above the base        assembly to provide a gap for access therebetween;    -   d) unfastening the bed support from the distributor by releasing        the fixing means;    -   e) removing the bed support from the column with a handling        device;    -   f) conducting maintenance on the column and/or the bed support        and/or said one or more seals;    -   g) returning the bed support to the column with said handling        device and fastening the bed support to the distributor; and    -   h) lowering the tube and the adapter assembly and reconnecting        the tube to the base assembly.

In one aspect, the method further comprises the steps of removing thedistributor from the column with the handling device and conductingmaintenance on the column and/or said distributor.

Preferably, the handling device is in the form of a cart having a pillarand comprising one or more arms projecting from said pillar forsuspending the bed assembly or distributor thereon. Preferably, the armsare extendable from the pillar. More preferably, the arms are verticallymovable on the pillar.

In one aspect, lifting the tube and the adapter assembly in step c)and/or lowering the tube and the adapter assembly in step h) is carriedout by means of an overhead hoist or crane.

In another aspect, lifting the tube and the adapter assembly in step c)and/or lowering the tube and the adapter assembly in step h) is carriedout by means of a drive system comprising one or more cylinders whichare mounted to or are integral with the column.

Optionally, the method additionally comprises the step of removing saidone or more cylinders from the column with the handling device.

Preferably, the step of removing the bed support from the column and/orthe step of returning the bed support to the column with the handlingdevice is carried out without substantially tilting the bed support.This reduces operator exposure beneath the suspended load andfacilitates mechanical handling of the bed support. The term ‘withoutsubstantially tilting’ as used herein means ‘tilting at an angle of nomore than 5° to the horizontal’.

Optionally, the step of removing the bed support from the column and/orthe step of returning the bed support to the column with the handlingdevice is carried out by tilting the bed support at an angle of morethan 5° to the horizontal. This may be necessary where the column hasdrive cylinders and the distance between any two drive cylinders is lessthan the diameter of the bed support.

In a third aspect of the present invention, there is provided a handlingdevice for use in a method of conducting maintenance on a chromatographycolumn as hereinbefore described, said device comprising a frame withwheels and a pillar, one or more arms projecting from said pillar forsupporting or suspending a chromatography column component therefrom,said one or more arms being movable vertically along the axis of thepillar by mechanical means, wherein the one or more arms has anattachment means for securing said column component thereto. Optionally,the device may additionally comprise a handle to facilitate steering.

In one aspect, the chromatography column component is selected from thegroup consisting of bed support, distributor, nozzle and drive cylinder.

In another aspect, the attachment means is a raised element on thesurface of the one or more arms for receipt of a fixing means in saidcolumn component. Preferably, the raised element is located centrally onone or more arms or at the intersection of the one or more arms. Morepreferably, the raised element is conically shaped to facilitateattachment of the column component to the arm.

In another aspect, the attachment means comprises a fixture for receiptof fixing means in the column component.

In a further aspect, the one or more arms additionally comprise a padfor resting the column component thereon. This prevents damage to thecolumn component. Preferably, the one or more arms are extendable.

In a further aspect, the one or more arms are removable and replaceablewith different arms to allow attachment of different column components.

In one aspect, the mechanical means for moving the one or more armsvertically along the axis of the pillar comprises a pulley or jack.Preferably, the mechanical means for moving the one or more armsvertically along the axis of the pillar is powered by electrical,pneumatic or hydraulic means.

In another aspect, the wheels are independently rotatable to improve themaneuverability of the handling device. Preferably, the wheels areindependently lockable. Preferably, the wheels are independentlylevelable; for example, by means of jacking devices attached to eachwheel. Levelable wheels provide easier and smoother operation of thehandling device on surfaces which are uneven such as clean rooms withsloping floors. More preferably, the wheels are powered by electricalmeans.

In a particularly preferred aspect, the one or more arms can rotate orpivot about the axis of the pillar to facilitate removal of the bedsupport or distributor where the column has drive cylinders and thedistance between any two cylinders is less than the diameter of the bedsupport or distributor.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the invention will become apparent fromthe following description taken in connection with the accompanyingdrawings in which:

FIG. 1 shows an embodiment of a column known in the art in a firstmaintenance position in cross sectional view.

FIG. 2 is a cross sectional view showing the same embodiment of thecolumn of FIG. 1 in a second maintenance position.

FIG. 3 is a schematic exploded front view of a column described inapplicant's U.S. Pat. No. 7,708,891.

FIG. 4 a is a schematic front view of a column described in U.S. Pat.No. 7,708,891; FIG. 4 b is a side sectional view of the column of FIG. 4a; and FIG. 4 c is a top plan view of the column of FIG. 4 a.

FIG. 5 a is a front perspective view showing the adapter assembly raisedand secured into position to provide a gap for access; FIG. 5 b showsremoval of the fastening means securing the backing plate to thedistributor and bed support.

FIG. 6 is a perspective view of a handling device used to remove/inserta distributor or a bed support from/into a column in accordance with themethod of the invention.

FIG. 7 a and FIG. 7 b are perspective views of the column of FIG. 5showing the removal of securing rods which fasten the bed support to thedistributor and backing plate.

FIG. 8 a and FIG. 8 b are perspective views showing the removal of thebed support from the column.

FIG. 9 a is a perspective view of a column with an inset showing alocking system; FIG. 9 b shows the column tube raised above the base andin the process of being locked into position.

FIG. 10 is a perspective view of a column with the column tube raisedand locked into position in readiness for maintenance.

FIG. 11 a and FIG. 11 b illustrate the process of removing the bedsupport from the column using a handling device.

FIG. 12 shows the bed support having been removed from the column inreadiness for maintenance.

FIG. 13 is a perspective view of the column of FIGS. 10 and 11 with thecolumn tube lowered awaiting bolting to the base.

FIG. 14 is a perspective view showing a handling device tilting a bedsupport to remove it from the gap in a column where the distance betweeneach of the drive cylinders is less than the diameter of the bedsupport.

FIG. 15 depicts a handling device carrying a drive cylinder.

FIG. 16 shows a handling device supporting a nozzle which has beenremoved from a column.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is concerned with a method and apparatus forconducting maintenance on a chromatography column. The invention isdescribed by reference to chromatography columns which utilise drivesystems to lift and/or lower the adapter assembly, and lift and/or lowerthe tube and adapter assembly. It will be understood that the inventioncould equally be described by reference to chromatography columnswherein these components are raised and/or lowered by an overhead hoistor crane. FIG. 1 shows a column 10 known in the art and described inU.S. Pat. No. 6,736,974 which permits maintenance within achromatography column without the need for a hoist or crane. The column10 comprises an elongated hollow cylindrical housing 12, or tube, havinga dispersion system 14 at the top and a collection system 16 at thebottom. The dispersion system 14 includes a cylindrical drum 18 havingan upper cylindrical plunger head or adapter 20 formed at the lower orinterior end (i.e. interior to the column). The adapter 20 is normallydisposed within the upper portion of tube 12 such as is illustrated inthe first operational position of FIG. 1. The adapter 20 may be moved bya drive system 34 such as the hydraulic arrangement shown in FIG. 1. Themovement of the adapter 20 allows for the compression of chromatographymedia in order to produce a packed media bed of the optimum heightwithin the column; a cavity 22 is formed between the dispersion andcollection systems 14, 16 and/or between the adapter 20 and the base 64.

The dispersion system 14 may include a mobile phase pathway connected toa liquid inlet 24 together with an inlet manifold 26 to distributeincoming liquid throughout a top portion of a media bed contained withinthe cavity 22. A bed support or inlet screen 28 is attached to theadapter 20 by connectors and/or by an inner clamp nut 30 which isaccessible from the cavity 22. The bed support 28 may be removedmanually for maintenance purposes by release of the clamp nut 30; thedistributor plate 31 may also be manually removable (see U.S. Pat. No.6,190,560 for a description of a distributor plate design).

A drive system is used to move the adapter 20 in an operational mode.The drive system is comprised of at least one and preferably three ormore, drive cylinders 34. The drive cylinders 34 move drive pistons 36which are coupled to the drum 18. A portion of the drive pistons 36 mayby threaded 38 to allow for the drive piston 36 to connect or couple toconnection arms 40 at specific locations relative to the drive piston 36such as with nuts 42, 44.

FIG. 1 shows a first maintenance position of the adapter 20 wherein theadapter 20 is raised a predetermined distance from a top 54 of thecavity 22 within the cylinder by means of the drive system 34 and piston36. The operator is thereby provided access with a hand to the centre ofthe drum 18 to release or affix nut 30 which retains the distributorplate 31 and bed support 28 to the adapter 20. The distributor plate 31and or/bed support 28 may then be removed manually, without the use of ahandling device, for maintenance. Once maintenance has been carried out,these components are then replaced by manual means, affixed to theadapter 20 and the adapter 20 lowered to return to an operational mode,nuts 42, 44 being reset to a proper operational configuration, ifnecessary.

In order to perform a second maintenance operation, such as removal ofthe lower bed support or screen 160 which is typically positioned sothat its outer edge 162 is between the tube 112 and the collectionsystem 116, the tube 112 may be raised by the drive system asillustrated in FIG. 2. The bolts which normally secure the tube 112 tothe base 164 are removed, and the nuts 142, 144 may be coupled to thepiston 136 to drive the tube 112 along with the drum 118 upwards asshown. A gap is thus provided which allows access for an operator toloosen nut 132, which affixes the lower bed support/screen 160 to thebase 164, and remove the bed support 160 manually for maintenance. Oncemaintenance has been completed, the bed support 160 is manuallyreplaced, affixed by nut 132 to the base 164 by the operator, and theprocess reversed to lower tube 112 and the drum 118 into an operationalposition.

Although not described below, it will be understood that the maintenanceof the column described in FIGS. 1 and 2 could be carried out inaccordance with the present invention.

The present invention will now be described with reference to FIGS. 3 to16; FIGS. 3 to 8 relate to providing access to the upper adapterassembly, FIGS. 9 to 14 to providing access to the base assembly formaintenance and FIGS. 15 and 16 to the use of the handling device of theinvention in carrying/lifting other column components not described inthe preceding figures.

FIG. 3 is a schematic exploded front view of a column described inapplicant's U.S. Pat. No. 7,708,891. The column is made of strong, inertmaterials such as stainless steel and other materials which are suitablefor use in a GMP environment typical of the pharmaceutical industry. Thecolumn 210 is supported on legs 204 having feet 206 which are adjustablein order to modify the height and/or the level of the column. The legs204 support the column 210 which comprises a cylindrical housing or tube212 separating a base assembly 263 at one end from an adapter assembly215 at the other. The tube 212 may typically be made from stainlesssteel, or other strong, inert materials. Adjacent to the adapterassembly 215 is a dispersion system comprising a nozzle 211 whichincludes a mobile phase pathway, for the introduction of buffer or othersuitable mobile phase liquids or chemicals/materials to be separated,and a liquid inlet 209. The tube 212 may be connected to the adapterassembly 215 and base assembly 263 by a drive system having one or morecylinders 234. The drive system may be a hydraulic system, as shown, ormay be powered by other suitable means, such as pneumatic or electricalmeans. The adapter assembly 215 is moveable within a cavity 222 of thetube 212 in an operational mode, for example, to pack or compress thebed of chromatographic media used to effect chromatographic separationof chemicals within the column. The adapter assembly 215 comprises anadapter flange 217, one or more distance pillars 219, a backing plate220 made typically of stainless steel, a distributor 231 which may takethe form of a plate having many channels to effect the even distributionof liquids, and a bed support 228 comprising a screen or mesh or filterand optionally a sealing ring (e.g. 229). The bed support may be made ofan inert plastic or metal material such as stainless steel. Thedistributor 231 and bed support 228 are fastened to each other byreleasable fixing means (not shown). Typical releasable fixing meansinclude, but are not limited to, a screw, a nut or a clamp. The fixingmeans 230 may only be accessed and thus released from the exterior faceof the backing plate 220, that is the face of the plate furthest awayfrom the cavity 222. In the present example, the nozzle 211 must firstbe removed to provide access to the fixing means 230. Additionalreleasable fixing means, accessible from the exterior face of thebacking plate, may optionally be employed to fasten the backing plate,distributor and bed support together. These fixing means can take theform of bolts inserted through corresponding holes around the perimeterof the components. Access from the exterior face of the backing plateavoids unnecessary exposure of the operator to a suspended or supportedload within the column.

The base assembly 263 comprises a backing plate 264 together with adistributor 266 and a bed support 268 fastened to each other byreleasable fixing means 269. The bed support 268 comprises a screen ormesh or filter and optionally a sealing ring (e.g. 274). The bed supportmay be made of an inert plastic or metal material such as stainlesssteel. Releasable fixing means 269 are, for example, a screw, a nut, abolt or a clamp; it will be appreciated that other releasable fixingmeans are also possible. As can be seen from the figure, the fixingmeans 269 secures bed support 268 and the distributor 266 through acentral hole in each component. The fixing means 269 is only accessibleand may therefore only be released from the exterior face of the backingplate 264. In FIG. 3, nozzle 272 must first be removed to provide accessto release fixing means 269. Additional releasable fixing means,accessible from the exterior face of the backing plate, may optionallybe employed to fasten the distributor and bed support together. Thesefixing means can take the form of bolts inserted through correspondingholes around the perimeter of the components. Access from the exteriorface of the backing plate 264 avoids operator exposure beneath asuspended load, were access only to be available from within theinterior of the column.

It will be understood that separation of chemical or biologicalmaterials on the column, when the tube 212 is full of chromatographicmedia, can be carried out in either a downward or upward flow. Thus, ina downward flow, liquid containing chemical or biological materials tobe separated is introduced through nozzle 211 and moves in a downwarddirection through the bed of media, to be collected in the collectionsystem at the base of the column via an outlet port (not shown). Inupward flow mode, liquid containing materials to be separated isintroduced via the bottom nozzle 272 and flows upwards through the mediabed to be collected at the top of the column via an outlet port (notshown). In the interests of clarity, the maintenance or servicing of thecolumn will be described in downward flow mode.

In order to conduct maintenance on the adapter assembly 215 ordistributor 231, the adapter assembly 215 is disconnected from thecolumn tube 212 by unscrewing the nuts which join the adapter flange 217to the upper column flange 213 a. The drive system then raises theadapter assembly 215 by means of cylinders 234 to allow for access tothe interior of the column for maintenance or service. The adapterassembly 215 is locked into position by means of locking rods 225 whichare aligned with and screwed into threaded holes in the locking system270. In this secured position, the adapter bed support and/or thedistributor may be removed from the column with a handling device (notshown) for maintenance once the fixing means are released, release beingeffected by removal from the exterior face of the column followingremoval of the nozzle 211 as described above. Once maintenance has beencarried out on the column (e.g. the bed support 228 has been replaced bymeans of the handling device), the column 210 is made operational againby reversing the above procedure: the adapter assembly 215 is releasedfrom the locking rod 225 and lowered by use of cylinders 234, and thenreconnected to the column tube 212 by replacing the nuts which join theadapter flange 217 to the upper column flange 213 a.

Maintenance or service is carried out on the bottom distributor 266 orbase assembly 263 by releasing the tube 212 from the base assembly 263and lifting the tube 212 and adapter assembly 215 with the aid of thedrive system. The bolts on the lower flange 213 b of the column tube 212which join it to the bottom backing plate 264 are removed. The columntube 212 and adapter assembly 215 are then lifted by means of the drivecylinders 234. The tube 212 and upper adapter assembly is secured inposition above the base with the cylinder brackets 236 by screwinglocking bolts through holes aligned in the locking pin 270, bracket 236and cylinder 234.

The bottom nozzle 270 is then disconnected from the back plate 264 anddistributor 266. The nozzle 270 is removed together with the distancering 235, to allow access to release the fixing means 269 which may bein the form of a nut. The nut 269 is removed from the exterior face ofthe backing plate 264, i.e. the face distant from the cavity 222, andthus eliminates operator exposure to a suspended or supported load. Ifadditional releasable fixing means, such as bolts inserted through thebacking plate, distributor and bed support as described above arepresent, these must be removed from the exterior face of the backingplate. The interior of the column may now be accessed for maintenance orservice, such as the replacement or cleaning of the bed support 268and/or O-rings, the bed support being removed with the aid of a handlingdevice (not shown). To return the column to an operational mode, theabove procedure is reversed.

FIG. 4 a is a schematic front view of a column of FIG. 3. The column 310is supported on legs 304 and has a base assembly 363 separated from anadapter assembly 315 by a tube 312. These components are made of strong,inert materials which are approved for GMP within the pharmaceuticalindustries, such as stainless steel. In the figure, the base assembly363 and adapter assembly are connected to a drive system which takes theform of three hydraulic cylinders 334. It will be understood that inother embodiments, different drive systems may be used to raise andlower the column, such as those powered by compressed air orelectricity. Furthermore, it is not essential that three cylinders areused, in some cases one being sufficient. The column 310 has a topnozzle 311 and a bottom nozzle for the introduction of liquids into thecolumn. An electrical unit 378 for controlling the drive system is alsoshown.

FIG. 4 b is a side sectional view of the column of FIG. 4 a showing oneof the hydraulic cylinders 334 in cross section. The cavity 322 forcontaining the bed of chromatographic media can be seen in crosssection. The liquid inlet 305, 375 and outlet 306, 376 of the top 311and bottom 372 nozzle are shown, for the introduction and removal ofliquids from the column 310. The cylinder 334 is connected to the baseassembly (comprising backing plate 364, distributor 366 and bed support368) and the adapter assembly 315 (comprising backing plate 320,distributor 331 and bed support 328).

FIG. 4 c is a top plan view of the column of FIG. 4 a which shows thethree hydraulic cylinders 334 and nozzle 311 with liquid inlet 305 andoutlet 306.

To raise the adapter assembly 315 for maintenance purposes, the nutsunder the upper column flange, which join the adapter 315 and columnflange 313 a, are loosened and removed. The drive system then lifts theadapter assembly 315 by means of the hydraulic cylinders 334. Theadapter assembly 315 is raised until the locking bolts are opposite thethreaded holes in the hydraulic cylinders 334 and the bolts screwed into secure the assembly in the service or maintenance position (see FIG.3).

FIG. 5 a is a front perspective view showing the adapter assembly 415raised and secured into position to provide a gap 427 for access to theinterior of the column for service or maintenance. The column 410 has adrive system comprising three hydraulic cylinders 434. The adapter bedsupport 428, the distributor 431 and the backing plate 420 are nowvisible; the bed support 428 can be unfastened from the distributor 431by releasing the fixing means (not shown) without accessing the gap 427.In order to describe this process, reference is made to FIG. 4 in thatthe nozzle 311 is first removed to provide access to remove theretaining nut (not shown) which secures bed support 328 to thedistributor 331 without accessing the gap 427. The fixing nut is removedfrom the exterior face of the backing plate 320.

FIG. 5 b shows release of the fixing means from the backing plate 420side of the adapter assembly using a spanner 446. The fixing means (inthe form of a retaining nut, obscured by the spanner) secures theadapter bed support to the distributor.

The bed support 428 is heavy and requires the use of a handling deviceto lift it once it has been separated from the adapter assembly.

An embodiment of the handling device 580 is shown in FIG. 6. The device580 is in the form of a trolley or cart with a vertical pillar 581supported on frame 582 having legs 583. The device 580 is made ofstrong, inert materials; such materials include, but are not limited to,stainless steel and other materials which are suitable for use in a GMPenvironment typical of the pharmaceutical industry. Extendable arms 585a, b, c project from the pillar 581 and can be raised or loweredrelative to the pillar 581 by mechanical or other means. In theembodiment shown, the arms 585 a, b, c are raised or lowered by a manualjacking mechanism (not shown) adjacent to the handle 584 which providesthe means to steer or control the device. The arms 585 a, b, c aredesigned to bear the weight of the distributor or bed support and areextendable to the diameter of these components. While the embodimentshown has three arms 585 a, b, c, it will be understood that the deviceis not so limited and that other embodiments may have less than or morethan three arms (e.g. one, two, four, five) depending on the individualdesign. Each arm 585 a, b, c has attachment means for securing a columncomponent thereto. In the embodiment shown, the attachment meanscomprises a fixture in the form of holes 587 a, b, c, at the extremitiesof the arms 585 a, b, c for bolting or securing of the distributorand/or bed support to the arms for safety, particularly duringtransport, removal and/or insertion of the column component. It will beunderstood that other attachment means can take many different forms,such as clips, clamps, fasteners etc. Pads (not shown) may be fitted tothe arms 585 a, b, c to minimise any risk of damage to the bedsupport/distributor when these components come into contact with thearms. A raised, central element, 588 (typically of conical shape) forreceipt of the central hole in the bed support or distributor provides ameans for centralising these components on the arms 585 a, b, c of thedevice 580. This element 588 may be fitted on either, or both, the upperor under side of the point where the arms 585 a, b, c intersect. Inoperation, the distributor and/or bed support is either suspended fromthe arms 585 a, b, c or supported on the arms. Pivotal wheels 586 alloweasy movement and manoeuvrability of the handling device 580. In theembodiment shown, the movement of the device 580 and theraising/extension of the arms 585 a, b, c are by manual means, but itwill be understood that other embodiments are possible which incorporatepowered systems (e.g. electrical, pneumatic or hydraulic systems) todrive the device 580 and lift/lower the arm 585. It will also beunderstood that in other embodiments of the handling device (not shown),arm 585 a is capable of pivoting or rotation around pillar 581 to enablethe arms 585 b and c to access a narrow gap between any two cylinders(e.g. 434 of FIG. 5 a) and remove/insert a bed support and/ordistributor which have a diameter which is greater than the distancebetween any two cylinders in the column (e.g. 434 of FIG. 5 a).

The operation of the device 580 in removing the bed support is shown inFIGS. 7 to 9.

FIG. 7 a and FIG. 7 b are perspective views of the column of FIG. 5showing the handling device of FIG. 6 supporting the bed support 628 onone or more arms 685. The arms 685 are raised into position below thebed support 628, care being taken not to damage the mesh of the bedsupport by positioning the pads (not shown) on the arms 685 of thehandling device 680 under the outer rim of the bed support 628, and thengently raising the arms 685 up to the bed support. Once the arms 685 arein position, the nuts on the threaded rods 633 that go through the backplate 620 and distributor 631 into the outer perimeter of the bedsupport 628 are loosened and the bed support can be removed on thehandling device. The rods 633 are initially loosened with a spanner andfinally removed by hand. As can be seen from the figures, the removal ofthe rods 633 is carried out from the exterior face of the backing plate620 without accessing the gap and thus without exposing the operator toa suspended or supported overhead weight.

FIG. 8 a and FIG. 8 b are perspective views showing the removal of thebed support 728 on the handling device 780 from the column 710. In FIG.8 a the bed support 728, borne on the arms 785 of the device 780, isremoved from the column 710 without substantially tilting the support728. The device 780 can then be moved away from the column (FIG. 8 b)and the arms 785 lowered in order that the bed support 728 can becleaned or replaced. Maintenance or servicing the column may now becarried out as required. For example, the bed support 728 may be cleanedor replaced, O-rings replaced and/or the distributor 731 may also beremoved for cleaning.

To return to an operational mode, the above procedure is simplyreversed. The bed support and distributor are returned to the column andaffixed to the backing plate, the nozzle reattached, and the adapterassembly lowered and bolted to the column tube.

Access to the bottom bed support and interior of the column will now bedescribed with reference to FIGS. 9 to 13. To access the bottom bedsupport, the tube is released from the base assembly by unscrewing thebolts that join it to the base and then lifting the tube and upperadapter assembly with the hydraulic cylinders.

FIG. 9 a shows a column 810 as previously described in FIGS. 3 to 5 andFIGS. 7 and 8. The bolts on the lower flange 813 b of the column tubewhich fasten the tube 812 to the bottom backing plate 864 are loosenedand unscrewed. The column tube 812 and adapter assembly 815 are liftedby the hydraulic cylinders 834 of the drive system until the holeindicated by ‘A’ is opposite the hole indicated by ‘B’ in the inset ofFIG. 9 a. Locking bolts 837 are then introduced into the aligned holesin the locking pin 870, bracket 836 and cylinder 834 to secure the tubeand adapter assembly in position (FIG. 9 b). After removal of the boltssecuring the tube 812 to the bottom backing plate 864, maintenance cannow be carried out on the column in the gap 827 created by raising thetube and adapter assembly.

FIG. 10 shows the column 910 with the tube 912 raised and mechanicallylocked to the cylinders 934 in readiness for maintenance. The bottomnozzle (not shown—see 272 in FIG. 3) is first removed from the backplate 964 by unscrewing the retaining bolts. The retaining nut (orfixing means) which fastens the bed support 968 to the distributor 966is released from the backing plate 964 side of the column 910. Ifadditional fixing means are present, such as bolts (not shown) whichfasten the bed support to the distributor and the backing plate, and arelocated on the perimeter of the backing plate, these are released fromthe backing plate face of the column.

The bed support 1068 can now be removed from the column by use of thehandling device as shown in FIG. 11 a and FIG. 11 b. The handling device(as described in FIG. 6 above) 1080 is wheeled into position where thearms 1085 are a few centimeters above the bed support 1068. The bedsupport 1068 has a number of threaded holes that correspond to the holesused to bolt the bed support to the backing plate 1064. The arms 1085 ofthe handling device 1080 have holes through which bolts are screwed intothe bottom bed support 1068; these holes are aligned to those of the bedsupport 1068 and bolts affixed to secure the bed support to the arms1085. Once attached, the bed support 1068 can be removed from the columnby raising the arms 1085 a few centimeters and wheeling the handlingdevice 1080 away from the column 1010. The bed support 1068 can now becleaned or new O-rings replaced as necessary. Generally the bed supportwill be moved away from the column, as shown in FIG. 12, lowered onto asurface (such as a trolley or workbench) and released from the arms 1185of the handling device 1180 to facilitate cleaning and servicing. Thedistributor (1066 in FIG. 11) can also be removed and serviced in asimilar manner using the handling device.

Once maintenance or servicing has been completed, the column is returnedto an operational mode by simply reversing the process as describedabove. This involves replacing the bed support/and or distributor in thecolumn, affixing the components to the backing plate, reattaching thenozzle, lowering the tube and adapter assembly. FIG. 13 shows the column1210 of FIG. 11 connected to the hydraulic control unit 1290 with thetube 1212 lowered and ready to be bolted to the backing plate 1264.

FIG. 14 illustrates the removal of a bed support 1368 from gap 1327 of acolumn 1310 in which the distance between any two drive cylinders 1334is less than the diameter of the bed support 1368. This is the case forexample in the column in FIG. 14 which has four drive cylinders 1334 orin the column described in FIGS. 1 and 2. In order to do so, arm 1385 ofhandling device 1380 is designed to rotate or pivot around joint 1389and, by so doing, substantially tilt the bed support 1368 such that itcan be removed or inserted between the cylinders 1334.

The handling device can also be used to remove or replace other columncomponents from/on a column. FIG. 15 illustrates the removal of a drivecylinder 1434 from column 1410 by affixing the cylinder to the arm 1485of the handling device 1480. The drive cylinder 1434 is secured to thearm 1485 of the handling device 1480 by attachment means 1487 in theform of screw holes for the receipt of the drive cylinder.

The nozzle 1511 can also be removed or affixed to the column by the useof the handling device 1580, as shown in FIG. 16. The nozzle is securedto the arm 1585 of the handling device 1580 by attachment means 1587 andmay then be transported to and/or lifted away from the column.

All patents, patent publications, and other published referencesmentioned herein are hereby incorporated by reference in theirentireties as if each had been individually and specificallyincorporated by reference herein. While preferred illustrativeembodiments of the present invention are described, one skilled in theart will appreciate that the present invention can be practiced by otherthan the described embodiments, which are presented for purposes ofillustration only and not by way of limitation. The present invention islimited only by the claims that follow.

What is claimed is:
 1. A method for conducting maintenance on achromatography column comprising: a) providing a chromatography columncomprising: a dispersion system comprising a nozzle including a mobilephase pathway connected to a liquid inlet; a tube with an adapterassembly and a base assembly, said adapter assembly moveable within acavity of said tube in an operational mode; the base assembly comprisinga distributor and a bed support fastened to each other by releasablefixing means; a collection system opposing the dispersion system; andone or more seals; b) releasing the tube from the base assembly; c)lifting the tube and the adapter assembly above the base assembly toprovide a gap for access therebetween; d) unfastening the bed supportfrom the distributor by releasing the fixing means; e) removing the bedsupport from the column with a handling device; f) conductingmaintenance on the column and/or the bed support and/or said one or moreseals; g) returning the bed support to the column with said handlingdevice and fastening the bed support to the distributor and the backingplate; and h) lowering the tube and the adapter assembly andreconnecting the tube to the base assembly.
 2. The method of claim 1,further comprising removing the distributor from the column with thehandling device and conducting maintenance on the column and/or saiddistributor.
 3. The method of claim 1, wherein said handling device isin the form of a cart having a pillar and comprising one or more armsprojecting from said pillar for suspending the bed support ordistributor thereon.
 4. The method of claim 3, wherein said arms areextendable from the pillar.
 5. The method of claim 3, wherein the armsare vertically movable on the pillar.
 6. The method of claim 1, whereinlifting the tube and the adapter assembly in step c) and/or lowering thetube and the adapter assembly in step h) is carried out by means of anoverhead hoist or crane.
 7. The method of claim 1, wherein lifting thetube and the adapter assembly in step c) and/or lowering the tube andthe adapter assembly in step h) is carried out by means of a drivesystem comprising one or more cylinders which are mounted to or areintegral with the column.
 8. The method of claim 1, wherein removing thebed support from the column and/or returning the bed support to thecolumn is carried out without substantially tilting the bed support. 9.The method of claim 1, wherein removing the bed support from the columnand/or returning the bed support to the column is carried out by tiltingthe bed support at an angle of more than 5° to the horizontal.